Fine-tuning helper Ts

If the transcriptional repressor Gfi-1 attended a dinner party, it would prevent its host from pairing a heavy red wine with a delicate fish. On page 329, Zhu et al. show how Gfi-1 (growth factor independent 1) stops helper T cells from secreting the wrong type of cytokine.

Gfi-1 expression (black) blunts Th17 development.

What cytokines a T cell produces helps determine the outcome of an infection. Naive CD4+ T cells differentiate according to the problem at hand. They tend to differentiate into type 2 helper T cells (Th2) when extracellular parasites lurk, Th1 when the culprit is intracellular, Th17 cells after invasion by bacteria and fungi, or regulatory T (T reg) cells when an inflammatory response requires dampening. Gfi-1 helps control that differentiation decision, show Zhu et al. Or as senior author William Paul says, “It keeps cells on the straight and narrow.”

This team previously reported that Th2-inducing cytokines, such as interleukin (IL)-4, induce Gfi-1, which then amplifies the Th2 response by triggering proliferation. Now they find that Gfi-1 also dampens the cells' tendencies toward the Th17 and T reg cell lineages. Gfi-1 inhibited production of IL-17 and blocked the expression of CD103, which is found on certain T reg cells. In a model of autoimmunity, mice that lacked Gfi-1 developed a preponderance of CD103-expressing T reg cells, thus delaying the onset of disease.

The protein prevented gene expression by binding to loci in the genes encoding IL-17 and CD103. Gfi-1 binding triggered histone modifications—most likely via its known interaction with the LSD1 histone demethylase—thus turning off gene expression. Gfi-1 expression was repressed by the cytokine TGFb, which drives Th17 and T reg cell differentiation, allowing induction of those cells when needed.

Examining expression of Gfi-1 in various human infections may help explain why the balance of cell types can sometimes be tipped in the wrong direction.